FR2813191A1 - New tocopherol derivatives containing 3-aminopropyl phosphate groups have useful physiological properties including skin healing and anti-ageing of biomembranes - Google Patents

Abstract

Derivatives of tocopherol which are hydrolyzable to tocopherol and 3-aminopropane phosphate by biological enzymes in a living organism. Derivatives of tocopherol (or their salts) of formula (I) are new. R1, R2 and R3 = H or Me, at least one being Me; A = -CH2-CH(CH3)- or -CH=C(CH3)-. An Independent claim is also included for the preparation of these derivatives.

Description

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BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to tocopherol derivatives and their salts, and the method of preparation thereof.

2. Description of prior art Cosmetics are intended to facilitate the styling of hair, to beautify skin and hair, to nourish them and to give them health. In particular, a great deal of research has lately been devoted to the inhibition of the formation of fine wrinkles on the skin by activation of the dermal cells. As a result, many products have been developed. For example, it has been reported that products comprising vitamins, for example retinol and ascorbic acid, proteins and flavanoids based on various plant and animal extracts, amino acids, epidermal growth factor and α-hydroxyl acid, are effective in inhibiting the formation of fine wrinkles on the skin. Such products find their application in cosmetics and similar products. However, most of the traditional products effective on fine wrinkles have defects, including low stability of the active ingredient and related products.

In addition, tocopherol, a fat-soluble type of vitamin, has been reported to have

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 bioactives comprising a protective function against the activity of free radicals which are harmful to the human body, the activation of cellular development and the triggering of collagen biosynthesis, anti-allergic effects and anti-inflammatory effects. Therefore, tocopherol has also been used as a component in cosmetics because of its bioactivities. However, the properties of instability, liposolubility and insolubility in tocopherol water have limited the use of tocopherol as a component in cosmetics.

Recently, many tocopherol derivatives have been developed to improve stability. For example, USP 4,564,686 disclosed that compounds produced by phosphatic esterification between tocopherol and ascorbic acid could enhance the stability of tocopherol. However, traditionally known tocopherol derivatives could only improve the stability of tocopherol. And they were just products simply combined by an esterification between tocopherol and compounds with similar physiological activities. Tocopherol derivatives introduced with compounds having other physiological activities have not yet been developed.

Under these circumstances, the present inventors have conducted extensive research to prepare tocopherol derivatives in which compounds having other physiological activities can be introduced, so that other bioactivities and

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 an improved stability of the tocopherol can thus be obtained. Accordingly, it has been discovered that tocopherol derivatives introduced with 3-aminopropanephosphate can be hydrolysed via biological enzymes in a living organism, and the hydrolysed products of tocopherol, tocopherol and 3-aminopropanephosphate, can perform different physiological activities. In addition, these tocopherol derivatives have both hydrophilic and hydrophobic groups and thus show improved stability in aqueous media. And these tocopherol derivatives also have a largely improved antioxidant effect compared to tocopherol.

dans laquelle, R1, RZ et R3 sont H ou un groupe méthyle et au moins une des positions sélectionnées dans le groupe comprenant les positions R1, RZ et R3 est un groupe méthyle ; et, SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide the tocopherol derivatives represented by the following formula (I), and their salts

wherein, R1, RZ and R3 are H or methyl and at least one of the positions selected from the group consisting of R1, RZ and R3 is methyl; and,

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 A is CH2 CH (CH3) - or CH = C (CH3) - The other object of the present invention is to provide a process for preparing the tocopherol derivatives mentioned above. The tocopherol derivatives are prepared by reacting tocopherol with phosphorus oxychloride in an equivalent ratio of 1: 1 to 1: 3, in the presence of an organic base, in an organic solvent; reacting the tocopherol dichlorophosphate produced by the reaction mentioned above with 3-aminopropanol, in the presence of an organic base, in an organic solvent; and hydrolyzing the products mentioned above.

The tocopherol derivatives according to the present invention can be hydrolysed by biological enzymes in a living organism to produce tocopherol and 3-aminopropanephosphate. And they are able to trigger physiological activities including healing of injured skin, prevention against aging of the bio-membrane, etc. In addition, the tocopherol derivatives according to the present invention have improved stability, good skin tolerance and an antioxidant effect superior to the previously known tocopherol and derivatives thereof. DETAILED DESCRIPTION OF THE INVENTION The tocopherol derivatives according to the present invention are products which can be hydrolysed by biological enzymes, they can thus release tocopherol and 3-aminopropanephosphate. they have

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 effects including prevention of biolipid oxidation and activation of collagen biosynthesis, and are also safe for the skin and may provide improved effects, for example increased skin elasticity and skin aging. In addition, the tocopherol derivatives according to the present invention have an excellent antioxidant effect and excellent stability both in aqueous and lipidic medium because they possess hydrophilic and lipophilic groups. Therefore, the tocopherol derivatives of the invention can have several applications, for example a cosmetic composition.

dans laquelle, R1, R2 et R3 sont H ou un groupe méthyle, et au moins une des positions sélectionnées dans le groupe comprenant les positions R1, R2 et R3 est un groupe méthyle ; et, A est CH2 CH(CH3)- ou CH=C(CH3)- Le procédé pour préparer les dérivés du tocophérol de formule générale (I) mentionnée ci-dessus comprend les étapes suivantes The tocopherol derivatives according to the present invention are represented by the following formula (I).

wherein, R1, R2 and R3 are H or methyl, and at least one of the positions selected from the group consisting of R1, R2 and R3 is methyl; and, A is CH 2 CH (CH 3) - or CH = C (CH 3) - The process for preparing the tocopherol derivatives of general formula (I) mentioned above comprises the following steps

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 (A) reacting tocopherol with phosphorus oxychloride at a temperature of about -10 to 50 ° C, in an equivalent ratio of 1: 1 to 1.3, in the presence of an organic base, in a solvent organic, to produce tocopherol dichlorophosphate; (B) reacting the tocopherol dichlorophosphate produced by the above-mentioned step (A) with 3-aminopropanol in the presence of an organic base in an organic solvent to produce 2-tocopherol-2H-1,3-tetrahydro- 2-oxazaphosphorine oxide; (C) filtering the solution containing the 2-tocopherol-2H-1,3,2-oxazaphosphorine-P-oxide produced by step (B), then adjusting the pH of the filtrate to a value of 1 to 5, and hydrolyzing the resulting products at a temperature of about 5 to 100 C, for about 1 to 10 hours; and (D) extracting the tocopherol derivatives with an organic solvent, and purifying them.

The process can be illustrated by the following reaction scheme (I).

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Le procédé pour préparer les dérivés du tocophérol représentés par le schéma de réaction (I) est expliqué en détail comme suit.

The process for preparing the tocopherol derivatives represented by reaction scheme (I) is explained in detail as follows.

(A) step of reacting tocopherol with phosphorus oxychloride, stirring at a temperature of -10 to 50 C, in an organic solvent, in the presence of an organic base, for 1 to 3 hours approximately to produce tocopherol dichlorophosphate; In step (A), it is preferred that the reaction of the tocopherol with phosphorus oxychloride be carried out in an equivalent ratio of 1: 1 to 1.3 ("ratio 1: 1--1.3"). When this ratio is less than 1: 1, the product subject to this

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 step can not be obtained. Whereas when this ratio is greater than 1: 1.3, by-products in excessive quantity, as well as the product which is the subject of this step, are obtained.

In this step, an intermediate complex of tocopherol and phosphorus oxychloride is produced with a yield equal to or greater than 95%, and ditocopherolphosphate as a by-product, a complex of 2: 1 ratio of tocopherol and oxychloride of phosphorus is produced with a yield equal to or less than 3%. However, the ditocopherphosphate can be removed simply by steps (B) and (C), and by a purification step, the triethylamine hydrochloride salt is removed by filtration from the reaction solution.

The organic base employed in this step may include, but is not limited to, pyridine and triethylamine. Of these, triethylamine may be preferable.

In addition, the organic solvent employed in this step may include, but is not limited to, dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, ethyl ether, and the like. and other inert solvents. Of these, tetrahydrofuran may be preferable. Meanwhile, at a temperature above 50 C, an equivalent ratio of two to more tocopherol can be reacted with an equivalent ratio of one to one of phosphorus oxychloride, thereby resulting in the production of a sub- product.

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 While at a temperature below -10 C, the reaction can continue slowly. It is therefore preferable to carry out the reaction of step (A) at a temperature of about -10 to about 50 ° C and, more preferably, at a temperature of about 0 to about 30 ° C.

In addition, when the reaction takes place for less than 1 hour, the quantities of unreacted products can increase, whereas when the reaction takes place for a duration equal to or greater than 3 hours, the product can change color. Therefore, the reaction time is preferably from 1 hour to about 3 hours.

The tocopherol dichlorophosphate obtained by filtration of the reaction solution is used for the next step.

(B) reacting the tocopherol dichlorophosphate represented by the formula (II) with 3-aminopropane in an organic solvent in the presence of an organic base; In step (B), the reaction between the tocopherol dichlorophosphate and the 3-aminopropanol is carried out at a temperature of -10 to 30 C, in a ratio equivalent of 1: 1 to 1, 3, in an organic solvent in the presence of an organic base. The above-mentioned reaction produces 2-tocopherol-2-tetrahydro-1H-1,3,2-oxazaphosphorine-P-oxide represented by formula (III). If the molar ratio of 3-aminopropanol to tocopherol dichlorophosphate (II) is less than 1.0, the reaction yield of step (B) decreases. In contrast, the by-products increase if this ratio is greater than 1.3. Therefore, the report

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 tocopherol dichlorophosphate with 3-aminopropanol is preferably from 1: 1 to 1.3.

In addition, the reaction rate may be slow at or below -10 ° C., and by-product production is increased at or above 30 ° C. Therefore, the reaction is preferably carried out. at a temperature of -10 to 30 C and more preferably at a temperature of 0 to 15 C.

In addition, the organic solvent and the organic base employed in this step are the same as those used in step (A).

(C) the step of filtering the 2-tocopherol-2H-1,3,2-oxazaphosphorine-P-oxide, then adjusting the pH of the filtrate to a value of 1 to 5, and then reacting the resulting products by hydrolysis at a temperature of about 5 to 100 C, for about 1 to 10 hours.

In the process according to the present invention, the filtrate of the reaction solution is concentrated under a reduced pressure, and the resulting residue can be hydrolysed using acid catalysts, for example hydrochloric acid and sulfuric acid, to adjust the hydrolysis conditions. Therefore, the PN bond can be hydrolysed by adjusting the pH to 1 to 5, preferably to 2 to 4, by addition of an acidic solution to the 2-tocopherteretetrahydro-2H-1,3,2-oxazaphosphorine P-oxide solution ( III), then maintaining at a temperature of about 5 to 100 C, and stirring. Therefore, 2-Copheroletrahydro-2H-1,3,2-oxazaphosphorine P-oxide

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 can be hydrolysed by filtering its solution, concentrating the filtrate, and adjusting the pH of the residue by adding an acid solution, and then reacting the resulting products to a temperature of about 5 to 100 ° C, and preferably approximately 10 to 40 ° C., for about 1 to 10 hours, preferably for about 2 hours. The rate of the reaction decreases when the reaction is carried out at a temperature of less than or equal to 5 ° C., whereas its P-O bond breaks at a temperature of greater than or equal to 100 ° C. In addition, the hydrolysis is not terminated when the reaction time is less than 1 hour, while the P-0 bond is broken for reaction times of more than 10 hours.

(D) extracting the tocopherol derivatives with an organic solvent and purifying them; The tocopherol derivatives are produced by mixing the solution obtained in stage (C) with an organic solvent, removing the impurities by several washings with water, drying the solution with sodium sulphate or magnesium sulphate. anhydrous, and removing the solvent. The organic solvent employed in this step is the same as those used in step (A).

The tocopherol derivatives proposed in the process of the invention may also be employed in the form of their salts, which are obtained by neutralization with an alkali or a base. A neutralizing agent may include, but is not limited to, alkali metal salts comprising the

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 sodium and potassium; salts of alkaline earth metals including calcium and magnesium; amine or ammonium salts including triethylamine. Preferred Embodiment of the Invention The present invention will be described in more detail by way of the following examples. However, these examples are offered for illustrative purposes only and should not be interpreted as limitations to the scope of the invention, the limits of which are clearly defined in the claims herein. Preparation Example 1 (Preparation of 3-aminopropyl-α-tocopherol phosphate) 9.87 g (6.44 mmol) of phosphorus oxychloride was placed in a flask and dissolved in 10 ml of tetrahydrofuran. The resulting solution was cooled to 3 C in an ice bath.

In another reactor, the solution of the mixture with 21.54 g (5.00 mmol) of α-tocopherol and 6.10 g (6.03 mmol) of triethylamine was diluted with 40 ml of tetrahydrofuran. Then, the solution was added dropwise to the above-mentioned solution of phosphorus oxychloride in tetrahydrofuran for about 1 hour. After this addition, the mixture was stirred for about half an hour, and triethylammonium chloride was removed by filtration. Then, the filtrate of tocopherol dichlorophosphate was cooled to 30C in a bath of

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 ice cream. In another reactor, 3.76 g (5 mmol) of 3-amino-1-propanol and 11.11 g (10.98 mmol) of triethylamine were diluted with 20 ml of tetrahydrofuran. Then, the solution was added dropwise to the above-mentioned filtrate for one (1) hour to produce 2-tocopherol-2-tetrahydro-1H-1,3,2-oxazaphosphorine P-oxide. After the addition, the mixture was stirred for half an hour. Then, the reaction solution was filtered to remove triethylammonium chloride. The filtrate was washed with sodium chloride solution, concentrated under reduced pressure. 40 ml of deionized water was then added to the concentrated residue and the pH was adjusted to 2 by adding hydrochloric acid. The reaction mixture was stirred at room temperature for about 2 hours, and was then washed by adding sodium chloride solution, which resulted in the separation of the organic portion. The organic portion was dried with 10 g of anhydrous magnesium sulfate. After filtration, the solvent was completely removed and 25 g of 3-aminopropyl-α-tocopherol phosphate was obtained in 88% yield.

 1H NMR (CDCl3, 300MHz); 0, 86 (t, 12H), 1.00-1.80 (m, 29H), 2.01 (s, 3H), 2.11 (s, 3H), 2.15 (s, 3H), 2. , 40- 2.50 (m, 2H), 2.70-2.80 (m, 2H), 3.90-4.00 (m, 2H), 7.80 (br, 3H)

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 Preparation Example 2 (Preparation of 3-aminopropyl-α-tocopherol phosphate) 23 g of 3-aminopropyl-5-tocopherol phosphate were obtained in 87% yield, by the same method of preparation as in Example 1, at the difference was that btocopheroldichlorophosphate was prepared using 20.13 g of 5-tocopherol.

 = 1H NMR (CDCl3, 300MHz); 0.86 (t, 12H), 1.00-1.80 (m, 29H), 2.03 (s, 3H), 2.55-2.65 (m, 2H), 3.10-3, (M, 2H), 4.10-4.20 (m, 2H), 7.91 (br, 3H) Preparation Example 3 (Preparation of a sodium salt of 3-aminopropyl-α-tocopherolphosphate) 1 g of 3-aminopropyl-α-tocopherol phosphate prepared according to Preparation Example 1 was dissolved with 30 ml of dioxane, then the pH was adjusted to 7 by adding 5% sodium carbonate solution. Then, by lyophilization, 3-aminopropyl-α-tocopherolphosphate sodium was obtained as a discolored yellow solid. Preparation Example 4 (Preparation of a potassium salt of 3-aminopropyl-α-tocopherol phosphate) 1 g of 3-aminopropyl-α-tocopherol phosphate prepared according to Preparation Example 1 was dissolved with 30 ml of dioxane, followed by pH was adjusted to 7 by adding potassium hydroxide. Then by

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 lyophilization, potassium 3-aminopropyl-α-tocopherol phosphate was obtained as a discolored yellow solid. Experimental example 1 Good tolerance of tocopherol derivatives If tocopherol derivatives were to be used as an ingredient in cosmetics, their good tolerance in a living organism is very important. The present invention therefore examined whether or not the tocopherol derivatives of the invention had toxic effects and whether they caused or did not cause body irritation. The product of Preparation Example 1 was dissolved in squalene to produce 10% solution sample and the sample was used in safety tests.

1-1. Acute oral toxicity test in mice: 1 ml / kg of the sample was administered to a total of ten (10) mice (five (5) males and five (5) females). As a result, no mouse deaths were observed. And the change in body weight noted after administration was also negligible.

1-2. Acute dermal toxicity test in mice and rabbits: 0.2 ml / kg of the sample was administered once percutaneously to a total of ten (10) mice (five males and five females). After two weeks of observation, none of the mice to which the sample was administered showed abnormal symptoms or variations in weight

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 body. When the same experiment was performed on rabbits, no abnormal symptoms and no change in body weight were observed in the rabbits to which the sample had been administered.

1-3. Primary dermal irritation test: 0.1 ml of test sample was applied to one area (2.5 cm x 2.5 cm) on the back of each rabbit out of 12 rabbits epilated 24 hours before. As a result, no skin irritation was observed.

1-4. Eye irritation test: The sample was diluted with saline to produce 2% of a sample to be examined, and 0.1 ml of the diluted solution was applied to the eye of each rabbit out of nine (9). ) rabbits. As a result, no ocular irritation of the cornea, iris and conjunctiva was observed.

1-5. Dermal sensitization test: One test was performed on six (6) guinea pigs (three males and three females) according to the technique of Maggnusson and Kligman. As a result, no skin abnormalities, for example erythema, edema or lentigos, were observed.

1-6. Epidermotest in humans a human patch test was performed on thirty (30) women aged 20 to 28 years, in good health, following the recommendations of the CFTA (The Cosmetic Toiletry and Fragrance Association, Inc. ., Washington, DC 20036, 1991). As a result, no primary irritation reaction was observed.

1-7. Epidermotest in humans by repeated aggression. tests in humans by patch-test were carried out on subjects, following the

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 CFTA recommendations. As a result, no renewed irritation or sensitive irritation was observed.

As mentioned in the results obtained in the safety tests presented above, the tocopherol derivatives according to the present invention are harmless products in cutaneous application. Experimental Example 2 Stability Test of Tocopherol Derivatives 3 g of each of the product of Preparation Example 1 and tocopherol were dissolved with 100 ml of cetylethyl hexanoate. While keeping them in a thermostatic bath at 60 C for six (6) months, the conservation of each compound was observed. Then, the residual proportion of each compound was analyzed using the high pressure liquid chromatography technique. At this stage, phenyl column, eluted solution of 70% aqueous tetrahydrofuran solution comprising 10 mM sodium dodecyl sulfate and 50 mM H 3 PO 4, flow rate of 1 ml / min and detection of 286 nm, were used as a condition. High pressure liquid chromatography analysis for Preparative Example 1. And ODS column, MeOH as eluted solution, flow rate of 1 ml / min and detection of 290 nm, were used as a condition of analysis by high pressure liquid chromatography for tocopherol observed as a control. The results are reported in Table 1. The degree of coloration of each compound was also observed

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to the naked. The results are shown in Table 2.

<tb> Table <SEP> 1.
<tb> Month <SEP> 1 <SEP> 2 <SEP> 3 <SEP> 4 <SEP> 5 <SEP> 6
<tb> Example <SEP> of <SEP> Preparation <SEP> 1
<tb> (Residual <SEP> ratio <SEP> (%)) <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100
<tb> Tocopherol
<tb> (Residual <SEP> residual <SEP> (%)) <SEP> 100 <SEP> 100 <SEP> 97 <SEP> 92 <SEP> 88 <SEP> 82 <SEP> 76
<tb> Table <SEP> 2.
<tb> Month <SEP> 1 <SEP> 2 <SEP> 3 <SEP> 4 <SEP> 5 <SEP> 6
<tb> Example <SEP> of <SEP> preparation <SEP> 1 <SEP> - <SEP> - <SEP> - <SEP> - <SEP> - <SEP> - <SEP> Tocopherol <SEP> - <SEP > - <SEP> - <SEP> + <SEP> + <SEP> ++ <SEP> ++
<tb> * <SEP> staining <SEP>: <SEP> -Yellow <SEP> discolored <SEP>;<SEP> + <SEP> low <SEP>;<SEP> ++ <SEP> average
<tb> +++ <SEP> strong
As shown by the data in Tables 1 and 2, the tocopherol derivatives of Preparation Example 1 did not change staining, while the tocopherol as a control experienced a four-color staining ( 4) or more than four (4) months. And quantitative analysis by NMR spectroscopy indicated that Preparation Example 1 was more stable.

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 Experimental Example 3 Effect on the Activation of Collagen Biosynthesis The effect on the activation of collagen biosynthesis was examined in vitro to evaluate the effect of the present invention on the skin, as compared to 3-aminopropanephosphate.

Child fibroblasts were seeded on tanks (24) (105 cells / reservoir). They were washed once with phosphate buffer solution. Then, Preparation Example 1 and 3-aminopropanephosphate as a control were processed by the concentration shown in Table 3 and incubated in a CO 2 incubator for 24 hours. Each supernatant was collected, and the procollagen variation was measured using a procollagen-type ELISA kit (I). The results are shown in Table 3. The value of the biosynthetic activity was calculated by comparison with 100, the value of an untreated sample.

<tb> Table <SEP> 3
<tb> Concentration <SEP> Activity <SEP> of
<tb> (%) <SEP> biosynthesis
<tb> 3-aminopropanephosphate <SEP> 10-4 <SEP> 146
<tb> Example <SEP> of <SEP> preparation <SEP> 1 <SEP> 10-6 <SEP> 141
As indicated by the results in Table 3, the tocopherol derivatives according to the present invention exhibit excellent collagen biosynthesis activity. Therefore, when the derivatives of the

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 tocopherol of the invention have been applied to the skin, it can be reported that the aging and oxidation of the bio-membrane can be prevented. Experimental Example 4 Hydrolysis by Biological Enzyme When applied to the skin percutaneously, the tocopherol derivatives according to the present invention were tested for their ability to be hydrolysed tocopherol and 3-aminopropanephosphate by a biological enzyme in a living organism. Phosphodiesterase was used as the biological enzyme, and a 1% aqueous solution of the mixture of Preparation Example 1 and Tween 20 in a 1: 9 ratio was prepared to serve as a test sample. After mixing the enzyme mentioned above, the test sample and the medium solution by stirring at 37 ° C. for 24 hours, an analysis of the proportion of hydrolysis of the tocopherol derivatives was carried out. using the high pressure liquid chromatography technique (MeOH tetrahydrofuran = 9: 1, reaction time = 13.695 min, tocopherol). As a result, 40% of the tocopherol derivatives of the invention were hydrolysed by the biological enzyme. However, since a certain amount of emulsifier was used to improve the insolubility of the compound of Preparation Example 1 in water, it would appear that the inactivation of the biological enzyme was of this nature. is increased. Therefore, the actual hydrolysis of tocopherol derivatives by a biological enzyme can

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 be performed in a much higher proportion. EXPERIMENTAL EXAMPLE 5 Measurement of antioxidant power with lard oil 2.0 g of lard oil was poured onto a petri dish, and at that time, tocopherol, preparation example 1 or tocopherol acetate, 40 mmol each, were added. The solution of the mixture was then kept in a dark room at 60 ° C. The oxidation rate of the blubber oil was determined by a daily measurement record of the variation in weight. The result is illustrated in FIG. 1. The lower the weight variability of the lard oil, the stronger the antioxidant power, because the increase in weight of the lard oil is related to the oxidation of the fat. bacon oil.

In the meantime, when the weight change of blubber oil was no longer observed, the oxidation rate was determined using the NMR spectroscopy technique. As a result, tocopherol, tocopherol acetate and untreated sample had an oxidation rate of about 90%. While the preparation example 1 according to the invention had only an oxidation rate of about 5%.

Experimental Example 6 Measurement of antioxidant power with linoleic acid 2.0 g of linoleic acid was poured onto a petri dish, and at that time tocopherol, the example

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 Preparation 1 or tocopherol acetate, 40 mmol each, were added. The mixture solution was then kept in a dark room at 60 ° C. The oxidation rate of linoleic acid was measured by daily measurement of the weight change. The result is illustrated in FIG. 2. The lower the weight variability of linoleic acid, the stronger the antioxidant power, because the increase in weight of linoleic acid is related to the oxidation of linoleic acid. linoleic acid.

In the meantime, when the weight variation of linoleic acid was no longer observed, the oxidation rate was determined using the NMR spectroscopy technique. As a result, tocopherol, tocopherol acetate and untreated sample had an oxidation rate of about 83%. While the preparation example 1 according to the invention only had an oxidation rate of about 3%.

As shown in Experimental Examples 5 and 6, it can be reported that the tocopherol derivatives of the invention have a much better antioxidant capacity than other tocopherol derivatives.

Although preferred embodiments of the present invention have been described in detail above herein, it should be understood that many variations and / or modifications to the basic concepts of the invention taught herein, and which may occur to those skilled in the art, will still fall within the scope of the spirit and scope of the present invention,

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 as defined in the appended claims.

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Claims (1)

wherein, R1, R2 and R3 are H or methyl and at least one of the positions selected from the group consisting of R1, R2 and R3 is methyl; and, A is CH2 CH (CH3) - or CH = C (CH3) - 2. A process for preparing said tocopherol derivatives according to claim 1, comprising the following steps: (A) reacting tocopherol with phosphorus oxychloride , at a temperature of -10 to 50 C, in an equivalent ratio of 1: 1. Tocopherol derivatives represented by the following general formula (I), or their salts  1 to 1.3, in the presence of an organic base, in an organic solvent, to produce tocopherol dichlorophosphate; (B) reacting the tocopherol dichlorophosphate produced by said step (A) with 3-aminopropanol, in the presence of an organic base, in an organic solvent to produce 2-tocopherol-2H-1,3,2-oxazaphosphorine P-oxide; <Desc / Clms Page number 25>  (C) filtering the solution containing the 2-octopheroletrahydro-2H-1,3,2-oxazaphosphorine P-oxide produced by said step (B), then adjusting the pH of the filtrate to a value of 1 to 5, and then hydrolyzing the solution at a temperature of about 5 to 100 C, for about 1 to 10 hours; and (D) extracting the tocopherol derivatives in the presence of organic solvent, and purifying them. The process according to claim 2, wherein said organic solvent employed in said steps (A), (B) or (D) is selected from a group consisting of methane dichloride, tetrahydrofuran, ethyl acetate, chloroform and ethyl ether. The method of claim 2, wherein said organic base employed in said steps (A) or (B) is pyridine or triethylamine.